To better understand how oncogenes initiate and maintain tumorigenesis, we have developed novel conditional transgenic models of tumorigenesis utilizing the Tet system. During the first grant cycle we have used these models to illustrate that the inactivation of a single oncogene can induce sustained tumor regression. Now, we will focus on further studies to investigate the mechanism by which MYC inactivation induces tumor regression. Our general hypothesis is that upon MYC inactivation, tumor cells recover physiologic programs of proliferative arrest, differentiation, apoptosis and angiogenesis. We know that this process is likely complex and will likely involve both cell autonomous and cell dependent processes, varies depending upon the type of tumor and can be influenced by the genetic context and the particular oncogene examined. In the midst of this complexity, we have chosen to focus on the examination mechanism by which the inactivation of the MYC oncogene induces the regression of MYC-induced T-ALL (lymphoblastic lymphoma). Specifically, we have found circumstances when tumors can escape dependence upon the MYC oncogene. Two observations that we have made may provide mechanistic insight into how MYC inactivation induces tumor regression and how tumors can escape dependence upon MYC. First, we found that lymphomas that have escaped dependence upon MYC appear to frequently possess already or have already acquired specific chromosomal abnormalities detected by Spectral Karyotypic Analysis (SKY). We have localized by array Comparative Genomic Hybridization (CGH) and Fluorescent In Situ Hybridization (FISH) a chromosomal translocation and deletion in chromosome 3 associated with tumor escape and now identified a candidate gene product. We hypothesize that this gene product facilitates the ability of tumors to escape from MYC dependence, which we now propose to evaluate. Second, we have found that loss of p53 function greatly impairs sustained tumor regression upon MYC inactivation. We hypothesize that restoration of p53 will permit MYC inactivation to induce sustained tumor regression. We present preliminary results that the loss of p53 impairs apoptosis and inhibition of angiogenesis associated with MYC inactivation, which we will now confirm. We will validate the relevance of our results to human tumors by taking advantage of our access a lymphoma repository as well as human T-ALL cell lines. The results of these studies will provide novel insights into the mechanism of "oncogene addiction" and will be useful towards the development of new treatments for T-ALL/lymphoblastic lymphoma. [unreadable] [unreadable] [unreadable] [unreadable]